1. Field of the Invention
This invention relates to technical fields relating to actions on pituitary adenylate cyclase activating polypeptide (hereinafter referred to as "PACAP") receptors. More specifically, the invention relates to use of peptides having a specific affinity to PACAP subtype 1 receptors.
2. Description of Related Art
PACAP was isolated from the hypothalami of sheep as a peptide activating adenylate cyclase (see, Biochem. Biophys. Res. Commun., 567-574 (1989); Arimura, A, et al., Regul. Peptides, 37, 287-303 (1992)). The amino acid sequence of PACAP is identified as follows (this is hereinafter referred to as "PACAP 38").
His Ser Asp Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln (SEQ ID NO: 4-NH.sub.2) 1 5 10 15 - Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu Gly Lys Arg Tyr Lys 20 25 30 - Gln Arg Val Lys Asn Lys-NH.sub.2 35
Thereafter, the existence of PACAP 27 consisting of the following shorter amino acid sequence at the N-terminal side was revealed:
His Ser Asp Gly Ile Phe Thr Asp Ser Tyr Ser Arg Tyr Arg Lys Gln (SEQ ID NO: 5-NH.sub.2) 1 5 10 15 - Met Ala Val Lys Lys Tyr Leu Ala Ala Val Leu-NH.sub.2 20 25
These PACAPs are considered to be members belonging to the secretin/glucagon/VIP family because in a comparison of amino acid sequences, homology of about 68% is observed between these PACAPs and the amino acid sequence composed of 28 amino acid residues at the N-terminal side of VIP.
Since PACAP exhibits homology to VIP as mentioned above, it was suggested that it signaled through receptors analogous to VIP receptors. It is now known that at least three subtypes of PACAP receptors exist. PACAP exhibits affinity but VIP does not exhibit affinity to PACAP type 1 receptors, while both PACAP and VIP exhibit affinity to PACAP type 2 and PACAP type 3 receptors. PACAP type 2 receptors and PACAP type 3 receptors are also called VIP type 1 receptors and VIP type 2 receptors, respectively.
PACAP is widely distributed in the body, for example, central nervous systems, testes, ovaries, adrenals, lungs, digestive tracts, pancreas, etc., and its action is considered to range widely. As to the PACAP receptors, it is recognized that the type 1 is expressed at a high level in brains, but at a low level at adrenals and scarcely at other principal tissues, whereas the type 2 is recognized to be expressed in lungs, brains, small intestines, livers, etc. and the type 3 is recognized to be expressed in lungs, stomachs, small intestines, pancreas, etc. As is seen from the above, it is known that some specificity exists in the tissue distribution of the PACAP receptors.
Agonists or antagonists having specific affinity only to the type 1 PACAP receptor have not yet been disclosed in technical literatures. Therefore, for determining, at the present point in time, whether or not targeted receptors among subtypes of PACAP receptors are type 1, a binding test wherein at least PACAP 38 or PACAP 27, and VIP are used in combination as ligands, etc. must be used.
Therefore, provision of compounds exhibiting specific affinity (or binding) to PACAP type 1 receptors will be desired even for merely examining functions of PACAP receptors.
On the other hand, part of the present inventors revealed that maxadilan derived from the salivary gland of Lutzomyia longipalpis, and its mutants, when infected into the epidermis of animals, cause erythema without itch and pain, and are extremely interesting peptides (see, for example, WO 91/00293; E. A. Lerner et al., J . Bio. Chem. 267, 1062-1066 (1992)). Further, they also revealed that a peptide (hereinafter referred to as "MAX") represented by the following amino acid sequence, among the mutants, exhibits a stronger erythema-forming action than natural maxadilan (see, for example, U.S. Pat. No. 5,480,864).
Gly Ser Ile Leu Cys Asp Ala Thr Cys Gln Phe Arg Lys Ala Ile Asp 16 (SEQ ID NO: 1) 1 5 10 15 - Asp Cys Gln Lys Gln Ala His His Ser Asn Val Leu Gln Thr Ser Val 32 20 25 30 - Gln Thr Thr Ala Thr Phe Thr Ser Met Asp Thr Ser Gln Leu Pro Gly 48 35 40 45 - Asn Ser Val Phe Lys Glu Cys Met Lys Gln Lys Lys Lys Glu Phe Lys 64 50 55 60 - Ala Gly Lys 67 65
They still further revealed that other various mutants of maxadilan also exhibit maxadilan-like biological activities, and part of them have agonistic binding ability to the surfaces of the cell membranes of tissues, particularly tissues derived from brains of mammals, and the other part have antagonistic binding ability thereto (see, U.S. Ser. No. 08/540,033).